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The Effects of Purine Compounds on the Isolated Aorta of the Frog Rana Temporaria Gillian E

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The Effects of Purine Compounds on the Isolated Aorta of the Frog Rana Temporaria Gillian E British Journal of Pharmacology (1996) 117, 873-878 B 1996 Stockton Press All rights reserved 0007-1188/96 $12.00 S The effects of purine compounds on the isolated aorta of the frog Rana temporaria Gillian E. Knight & 'Geoffrey Burnstock Department of Anatomy and Developmental Biology and Centre for Neuroscience, University College London, Gower Street, London WC1E 6BT 1 In the isolated aorta of the frog, Rana temporaria, adenosine concentration-dependently, endothelium-independently relaxed adrenaline pre-constricted vessels. None of the adenosine analogues including D-5'-(N-ethylcarboxamide) adenosine (NECA), R- and S-N6-(2-phenylisopropyl) adenosine (R- and S-PIA) and 2-chloroadenosine (2-CA), or the more selective Al, A2 and A3 agonists cyclopentyladenosine (CPA), CGS 21680 and Ml-(3-iodobenzyl) adenosine-5'-N-methylcarboxamide (IB-MECA) respectively, had any effect. 2 The non-selective adenosine antagonist, 8-p-sulphophenyl-theophylline (8-pSPT; 30 giM) failed to inhibit adenosine relaxations, as did NG-nitro-L-arginine methyl ester (L-NAME; 0.1 mM) and indomethacin (30 gM). 3 Adenosine 5'-triphosphate (ATP), ca,f,-methylene ATP (a,#-MeATP), ,B,y-methylene ATP (fl,y- MeATP), 2-methylthio ATP (2-MeSATP) and uridine 5'-triphosphate (UTP) all concentration- dependently contracted the frog aorta. ATP and a,,B-MeATP were equipotent and more potent than UTP and ,B,y-MeATP; 2-MeSATP had little activity. 4 The P2-purinoceptor antagonist, suramin (0.1 mM) inhibited contractions to x,,B-MeATP but not to ATP. Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 30 gM) also inhibited contractions to a,,B-MeATP but not to ATP. Contractions to ATP were, however, inhibited by indomethacin (30 gM). 5 In conclusion, in the frog aorta there appears to be a novel subclass of P1-purinoceptor mediating vasodilatation, although like the A3 subclass it is not blocked by methylxanthines; a P2-purinoceptor mediates vasoconstriction which resembles a P2X subtype, based on the agonist potency of a,,B-MeATP being more potent than 2-MeSATP (UTP has moderate activity) and PPADS is an effective antagonist. There is no evidence for the presence of a P2Y-purinoceptor, mediating vasodilatation, in this preparation. Keywords: Frog aorta; adenosine; ATP; purinoceptor Introduction Purine nucleotides and nucleosides have long been known to agonist at this receptor (Jacobson et al., 1993; Gallo- have effects on the cardiovascular system of mammals. Ade- Rodriguez et al., 1994) and D-5'-(N-ethylcarbox nosine was shown to inhibit activity in mammalian hearts in amide) adenosine (NECA) and N6-(2-phenylisopropyl) ade- 1929 by Drury & Szent Gy6rgyi, and it was observed that ATP nosine (PIA) are equipotent, but it is resistant to methyl- was more effective at causing heart block in the guinea-pig xanthine blockade. P2-purinoceptors were initially divided into than adenosine (Drury, 1936). Further investigations into the P2x and P2Y subclasses (Burnstock & Kennedy, 1985); other effect of adenosine and ATP on the cardiovascular system subdivisions have since been recognised, P2Z, P2T and P2u followed (Gaddum & Holtz, 1933; Richards, 1934; Green & classes (Gordon, 1986; Hoyle & Burnstock, 199la; Stone, 1991; Stoner, 1950) resulting in detailed documentary evidence of the Hoyle, 1992; O'Connor, 1992). Additional subdivisions have important role of both adenosine and ATP in the maintenance been proposed, P2R, P2S and P3, but these have not been widely of mammalian vascular tone (see Olsson & Pearson, 1990) via accepted (see Hoyle & Burnstock, 1991a, b; Stone, 1991). In the the heart and systemic vascular systems (Su, 1981; 1985; most recent proposal for purinoceptor subclassification by Burnstock & Kennedy, 1986; Burnstock, 1987a,b; 1989; 1990b; Abbracchio & Burnstock (1994), adopted in principle by the Ralevic & Burnstock, 1991). IUPHAR Nomenclature Committee (see Fredholm et al., Once it was recognised that adenosine and ATP had differ- 1994), two families of purinoceptors are recognised, P2X ent effects on mammalian systems and were therefore acting via (ligand-gated cation channels) and P2Y (G-protein mediated), separate receptors, a formal classification was proposed each with their own subclasses, P2XI4 and P2YI-7. (Burnstock, 1978). Receptors selective for adenosine and ade- Both P,- and P2-purinoceptors have important actions on nosine monophosphate (AMP) were designated as PI-pur- the cardiovascular system. Generally, adenosine dilates mam- inoceptors and those selective for ATP and adenosine malian blood vessels by acting on A2-receptors located on the diphosphate (ADP) called P2-purinoceptors. P1-purinoceptors, smooth muscle (Berne et al., 1983; Burnstock & Kennedy, 1986; susceptible to methylxanthine blockade, were divided into Al- Collis, 1989) whereas activation of Al-receptors often mediates and A2-receptors (Van Calker et al., 1979; Londos et al., 1980). prejunctional inhibition (Verhaeghe et al., 1977). Stimulation More recently an A3-receptor subclass has been cloned of P2x-purinoceptors mediates vasoconstriction via an action (Meyerhof et al., 1991; Zhou et al., 1992), M-(3-iodobenzyl)- on receptors located on the smooth muscle (Burnstock & adenosine-5'-N-methylcarboxamide (IB-MECA) is a selective Kennedy, 1986; Burnstock, 1990a, c) and activation of en- dothelial P2Y-purinoceptors results in vasodilatation, via the release of endothelium-derived relaxing factor (EDRF) now known to be nitric oxide (NO) (De Mey & Vanhoutte, 1981; 'Author for correspondence. Houston et al., 1987; Pearson & Gordon, 1989) and prostacy- 874 G.E. Knight & G. Burnstock Adenosine dilates and ATP constricts the frog aorta clin (Moncada & Vane, 1979), although P2Y-purinoceptors presence of the P2-purinoceptor antagonists, suramin (0.1 mM) have been identified on the vascular smooth muscle of some and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid vessels (Mathieson & Burnstock, 1985; Brizzolara & Burn- (PPADS; 30 gM) and the prostanoid inhibitor, indomethacin stock, 1991). (30 mM). All antagonists were allowed to equilibrate for While the effects of both adenosine and ATP have been 20 min before concentration-response curves were repeated. extensively studied on mammalian systems, there is, in con- trast, only limited information available on the role of purines Drugs used in the control of the cardiovascular system of lower verte- brates. A presynaptic Al-receptor has been identified, stimu- Adrenaline bitartrate, adenosine, NECA, R-PIA, S,PIA, 2- lation of which inhibits sympathetic nerve activity to arterioles CA, ATP, cx,f3-MeATP, f3,y-MeATP, UTP, ACh, in- of frog cutaneous muscle (Fuglsang et al., 1989). There are domethacin, L-NAME, dimethyl sulphoxide (DMSO) and as- several studies examining the effect of purine compounds on corbic acid were supplied by Sigma Chemical Co; 2-MeSATP, the amphibian heart. P1-purinoceptors have been demon- CPA, CGS 21680 (2-[-p-(2-carboxyethyl) phenethylamino]-5'- strated in frog heart (Burnstock & Maghji, 1981; Lazou & N-ethylcarboxamido adenosine) and 8-pSPT by Research Beis, 1987). P2-purinoceptors have been identified in axolotl, Biochemicals Inc.; IB-MECA was the kind gift of Prof. K. frog and toad atria (Meghji & Burnstock, 1983a, b; Hoyle & Jacobson (NIH, U.S.A.), suramin was the kind gift of I.C.I. Burnstock, 1986). A non-adrenergic, non-cholinergic (NANC) and PPADS a kind gift from Prof. Lambrecht (Frankfurt, excitatory transmission has been demonstrated in the frog Germany). Adrenaline was dissolved in 100 gM ascorbic acid; heart (Donald, 1985) which is mediated by a P2-purinoceptor IB-MECA in DMSO to give a stock solution, the first dilution (Burnstock & Meghji, 1981), ATP being a cotransmitter with in 50% DMSO/50% distilled water, and subsequent dilutions adrenaline (Hoyle & Burnstock, 1986; Bramich et al., 1990). in distilled water; indomethacin in 0.2 M NaCO3 solution and Studies have revealed PI-purinoceptors on the coronary artery NECA, R- and S-PIA, CPA and CGS 21680 in DMSO to of trout and skate (Small et al., 1990; Farrell & Davie, 1991) produce a stock solution, with subsequent dilutions in distilled and trout gill vasculature (Colin & Leray, 1979; Colin et al., water. All other drugs were dissolved in distilled water. 1979), dogfish atria and aorta (Meghji & Burnstock, 1984; Evans, 1992). ATP has been shown to dilate the portal vein of Statistical analysis the lizard (Ojewole, 1983). The present investigation was car- ried out to study the effects of adenosine and ATP in the iso- Vasodilator responses are expressed as mean % relaxation of lated aorta of the frog and to identify purinoceptor subtypes the adrenaline (EC50 concentration) contraction + standard using agonist potency orders and selective antagonists. error (s.e.) (n) and vasoconstrictor responses are expressed as a mean maximum tension developed in g or as a % of the maximum response in the absence of antagonist+s.e. (n). Methods Significance was tested by analysis of variance followed by Tukey's test, or Student's paired t test. A probability of Frogs (Rana temporaria) of either sex, supplied by Blades P < 0.05 was taken as significant. Biological, Cowden, Edenbridge, U.K., were stunned and de- capitated. The frog was pithed and the brain destroyed with a metal seeker. The aortic branches were rapidly removed and Results placed in a physiological saline solution. Ring segments of approximately 4-5 mm, one from each arch, were dissected Vasodilator response to adenosine free and mounted in 10 ml organ baths containing gassed (95% 02/5% C02) saline of the following composition (mM): Adrenaline, known to be the principle transmitter in sympa- NaCl 111.1, KC1 1.88, NaH2PO4 0.08, NaHCO3 2.35, CaCl2 thetic nerves in amphibians (see Burnstock, 1969), concentra- 1.08 and glucose 1.11. All experiments were carried out at tion-dependently constricted isolated preparations of frog room temperature, 23 + 1.00C. aorta. The EC50 value for each preparation was calculated and Segments of aorta were mounted horizontally in the organ this concentration was used to constrict the vessel to study bath by inserting two tungsten wires through the lumen of vasodilator responses. The mean pD2 (-log EC50 value) for the vessel.
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